The Temporal Relationship between Blood–Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia
Abstract
:1. Introduction
2. Materials and Methods
- Ethics approval:
- Animals:
- Animal source and housing
- Surgery protocol: modified Rice–Vannucci model to induce HI injury:
- Post-mortem and brain processing
- Immunohistochemistry
- Immunohistological assessment:
area of the contralateral hemisphere
- Microbleed criteria
- (a).
- Non-linear red blood cells.
- (b).
- Red blood cells surrounded by parenchyma.
- (c).
- Erythrocytes not contained within a vessel.
- (d).
- A total of >5 cells clustered together, <10 mm.
- (e).
- Exclusion of red blood cells from the choroid plexus and ventricles.
- Statistical analysis:
3. Results
- Animal Cohort Characteristics
- Progression of neuropathology over time following perinatal HI.
- Progression of microglial activation in the brain over time following perinatal HI
- Progression of HI-mediated BBB breakdown: Extravasation of peripheral blood
- Progression of HI-mediated BBB breakdown: Structural integrity
- Microbleed correlation analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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6 h | 12 h | 24 h | 72 h | |
---|---|---|---|---|
Number (n) | ||||
Sham | 9 | 9 | 6 | 5 |
HI | 10 | 9 | 5 | 7 |
Sex ratio (F/M) | ||||
Sham | 6/3 | 5/4 | 1/5 | 2/3 |
HI | 5/5 | 6/3 | 1/4 | 4/3 |
Brain weight (g) | ||||
Sham | 0.97 ± 0.018 | 0.994 ± 0.016 | 0.87 ± 0.005 | 1.05 ± 0.012 |
HI | 0.997 ± 0.015 | 1.006 ± 0.017 | 0.835 ± 0.021 | 1.018 ± 0.017 |
Pup mortality | ||||
Sham | 0 | 0 | 0 | 0 |
HI | 0 | 0 | 0 | 0 |
Antibody | Target | Antigen Retrieval | Block Endogenous Peroxidases | Protein Block | Primary Antibody | Primary Antibody Concentration | Secondary Antibody |
---|---|---|---|---|---|---|---|
NeuN (Merck Millipore, Burlington, MA, USA; cat#MAB377) | Neurons | Heated in 0.1 M of citric acid buffer (pH 6) for 15 min and left to cool for 20 min | 3% H202 in PBS for 10 min | 5% NGS +1% BSA in PBS for 30 min | Mouse anti-NueN in 1% BSA + 0.3% TX-PBS | 1:1000 | Goat anti-mouse, biotinylated IgG |
Iba-1 (Wako Pure Chemical Industries, Osaka, Japan; cat#019-19741) | Microglia | Heated in 0.01 M of citric buffer (pH 6) for 15 min and left to cool for 20 min | 3% H202 in PBS for 30 min | 10% NGS in 0.1 M PBS for 30 min | Rabbit anti-Iba-1 in 0.2% TX-PBS | 1:1000 | Goat anti-rabbit, biotinylated IgG |
Glut-1 (Sigma-Aldrich, St. Louis, MI, USA; cat#ABI4683) | Glucose transporters | Heated in 0.01 M of citric buffer (pH 6) for 20 mis and left to cool for 20 min | 0.3% H202 in PBS for 15 min | DAKO protein-free blocker for 1 h | Rabbit anti- Glut-1 in PBS | 1:200 | Goat anti-rabbit, biotinylated IgG |
Glial fibrillary acidic protein (GFAP) (Sigma-Aldrich, St. Louis, MI, USA; cat#G3893) | Reactive astrocytes | Heated in 0.01 M of citric acid buffer (pH 6) for 9 min and left to cool for 15 min | 0.3% H202 in 50% methanol for 20 min | 5% NGS in PBS for 30 min | Mouse anti-GFAP in 0.3% in TX-PBS | 1:400 | Goat anti-mouse, biotinylated IgG |
Laminin (Sigma-Aldrich, St. Louis, MI, USA; cat#NB300-144) | Basal lamina | 1:500 proteinase K for 30 min at 37 degrees, humidified | N/A | 10% NGS in 0.1% TX-PBS for 30 min | Rabbit anti-laminin in 0.1% PBST and 2% NGS | 1:200 | Goat anti-rabbit-488 |
Albumin (Waltham, MA, USA; A110-134A) | Albumin | N/A | 3% hydrogen peroxide in 50% methanol for 10 min | 5% NRS + 3% BSA in PBS-TX for 90 min | Sheep anti-rat albumin in 0.1% TX-PBS and 0.5% fish gelatin | 1:2000 | Rabbit anti-sheep |
Outcome | R2 Value | p-Value | Confidence Interval |
---|---|---|---|
Tissue Loss | |||
6 | 0.003856 | 0.7948 | −1.415, 1.099 |
12 | 0.008832 | 0.7107 | −0.7536, 0.5258 |
24 | 0.5758 | 0.0178 | 0.5229, 3.969 |
72 | 0.03043 | 0.5877 | −2.060, 3.444 |
Apoptosis | |||
6 | 0.6381 | <0.0001 | 0.05811, 0.1353 |
12 | 0.2987 | 0.0127 | 0.01686, 0.1229 |
24 | 0.5821 | 0.0168 | 0.08507, 0.6160 |
72 | 0.5488 | 0.0058 | 0.2593, 1.177 |
Neuronal Loss | |||
6 | 0.4963 | 0.0008 | −21.35, −6.823 |
12 | 0.8546 | <0.0001 | −13.09, −8.392 |
24 | 0.7372 | 0.0030 | −18.51, −5.629 |
72 | 0.5729 | 0.0044 | −27.99, −6.816 |
Resting Microglia | |||
6 | 0.1253 | 0.1257 | −0.3446, 0.04604 |
12 | 0.7597 | <0.0001 | −0.6013, −0.3252 |
24 | 0.3116 | 0.1183 | −1.668, 0.2353 |
72 | 0.5207 | 0.0081 | −2.228, −0.4307 |
Intermediate Microglia | |||
6 | 0.4138 | 0.0022 | 0.4358, 1.687 |
12 | 0.8465 | <0.0001 | 1.030, 1.630 |
24 | 0.1907 | 0.2399 | −0.4374, 1.477 |
72 | 0.1855 | 0.1622 | −0.4843, 0.09319 |
Activated Microglia | |||
6 | 0.3543 | 0.0056 | 0.2127, 1.070 |
12 | 0.8247 | <0.0001 | 0.5544, 0.9131 |
24 | 0.5861 | 0.0162 | 0.2473, 1.739 |
72 | 0.5959 | 0.0033 | 2.594, 9.764 |
Total Microglia | |||
6 | 0.2622 | 0.0210 | 0.2590, 2.799 |
12 | 0.7849 | <0.0001 | 1.722, 3.045 |
24 | 0.1232 | 0.3543 | −1.239, 3.029 |
72 | 0.5158 | 0.0085 | 1.514, 8.025 |
Basal Lamina Integrity | |||
6 | 0.1603 | 0.0803 | −1437, 89.98 |
12 | 0.4751 | 0.0016 | −2097, −596.6 |
24 | 0.3064 | 0.1220 | −1825, 268.3 |
72 | 0.3470 | 0.0439 | −2330, −39.61 |
Tight-Junction Integrity | |||
6 | 0.07908 | 0.2297 | −0.1054, 0.02702 |
12 | 0.2830 | 0.0231 | −0.05113, −0.004337 |
24 | 0.4918 | 0.0353 | −0.1409, −0.006748 |
72 | 0.6159 | 0.0025 | −0.1883, −0.05368 |
Astrogliosis | |||
6 | 0.000642 | 0.9155 | −97,873, 88,340 |
12 | 0.0173 | 0.6028 | −36,306, 60,560 |
24 | 0.511 | 0.0302 | 12,014, 177,005 |
72 | 0.01398 | 0.7143 | −143,535, 201,924 |
Glucose Transport Expression | |||
6 | 0.01526 | 0.6039 | −47.72, 79.76 |
12 | 0.03846 | 0.4354 | −39.92, 88.32 |
24 | 0.01302 | 0.7701 | −24.01, 31.09 |
72 | 0.01084 | 0.7474 | −41.57, 30.81 |
Albumin Extravasation | |||
6 | 0.5837 | 0.0006 | 0.5245, 1.509 |
12 | 0.5975 | 0.0012 | 0.6644, 2.082 |
24 | 0.4710 | 0.0412 | 0.07557, 2.784 |
72 | 0.6678 | 0.0012 | 1.183, 3.520 |
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Jithoo, A.; Penny, T.R.; Pham, Y.; Sutherland, A.E.; Smith, M.J.; Petraki, M.; Fahey, M.C.; Jenkin, G.; Malhotra, A.; Miller, S.L.; et al. The Temporal Relationship between Blood–Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia. Cells 2024, 13, 660. https://doi.org/10.3390/cells13080660
Jithoo A, Penny TR, Pham Y, Sutherland AE, Smith MJ, Petraki M, Fahey MC, Jenkin G, Malhotra A, Miller SL, et al. The Temporal Relationship between Blood–Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia. Cells. 2024; 13(8):660. https://doi.org/10.3390/cells13080660
Chicago/Turabian StyleJithoo, Arya, Tayla R. Penny, Yen Pham, Amy E. Sutherland, Madeleine J. Smith, Maria Petraki, Michael C. Fahey, Graham Jenkin, Atul Malhotra, Suzanne L. Miller, and et al. 2024. "The Temporal Relationship between Blood–Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia" Cells 13, no. 8: 660. https://doi.org/10.3390/cells13080660
APA StyleJithoo, A., Penny, T. R., Pham, Y., Sutherland, A. E., Smith, M. J., Petraki, M., Fahey, M. C., Jenkin, G., Malhotra, A., Miller, S. L., & McDonald, C. A. (2024). The Temporal Relationship between Blood–Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia. Cells, 13(8), 660. https://doi.org/10.3390/cells13080660